ClinVar Miner

Submissions for variant NM_000077.4(CDKN2A):c.334C>G (p.Arg112Gly) (rs876660436)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000213802 SCV000277860 likely pathogenic Hereditary cancer-predisposing syndrome 2016-07-21 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbsnp, esp, 1000 genomes),Moderate segregation with disease (at least 3 informative meioses) for rare diseases.,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Deficient protein function in appropriate functional assay(s)
Invitae RCV000554207 SCV000637414 pathogenic Hereditary cutaneous melanoma 2017-06-09 criteria provided, single submitter clinical testing The CDKN2A gene encodes two different proteins, p16INK4a and p14ARF, which are translated from alternative transcripts that have different open reading frames. This sequence change replaces arginine with glycine at codon 112 of the CDKN2A (p16INK4a) protein (p.Arg112Gly). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and glycine. Alternatively, this sequence change replaces proline with arginine at codon 126 of the CDKN2A (p14ARF) protein (p.Pro126Arg). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with melanoma in multiple families (PMID: 10398427, 16307646, 21462282), and has been reported in additional families and individuals with melanoma (PMID: 12072543, 16905682, 16896043, 17047042, 22841127). ClinVar contains an entry for this variant (Variation ID: 233484). Experimental studies have shown that Arg112Gly in p16INK4a affects protein function, which reduces binding to CDK4 and alters sub-cellular localization in vitro (PMID: 11518711, 20340136), but has conflicting results on cell-cycle arrest (PMID: 21462282, 12606942). In addition, experimental studies have shown that Pro126Arg in p14ARF slightly affects hdm2 binding, but behaves similar to wild-type in hdm2 induction and localization in vitro (PMID: 11518711). For these reasons, this variant has been classified as Pathogenic. While the evidence indicates that this variant confers risk of developing CDKN2A (p16INK4a)-associated conditions, its association with risk for developing CDKN2A (p14ARF)-associated conditions is still unclear.

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